For fifth-seeded Isner, the runner-up in Houston last year, the title is his sixth on the ATP Tour but his first on clay and his performance drew the praise of his opponent.
"He did a really good job today. He played aggressive," said Almagro, who like Isner was playing in his first final of 2013.
"He served like normal, but today was tough for me. I want to congratulate him, because he's a really good player and a good person and I think he did a good job this week."
World number 23 Isner broke the 12th-ranked Spaniard three times to secure the win 81 minutes.
Isner finished with seven aces to Almagro's five and set a tournament record with 64 aces during his run to the title, beating Pete Sampras's mark of 60 in 2002.
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